New strategies to enhance the efficiency and precision of drug discovery

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 11, 2025

Drug discovery plays a crucial role in medicinal chemistry, serving as the cornerstone for developing new treatments to address wide range of diseases. This review emphasizes significance advanced strategies, such Click Chemistry, Targeted Protein Degradation (TPD), DNA-Encoded Libraries (DELs), and Computer-Aided Design (CADD), boosting drug process. Chemistry streamlines synthesis diverse compound libraries, facilitating efficient hit lead optimization. TPD harnesses natural degradation pathways target previously undruggable proteins, while DELs enable high-throughput screening millions compounds. CADD employs computational methods refine candidate selection reduce resource expenditure. To demonstrate utility these methodologies, we highlight exemplary small molecules discovered past decade, along with summary marketed drugs investigational that exemplify their clinical impact. These examples illustrate how techniques directly contribute advancing chemistry from bench bedside. Looking ahead, Artificial Intelligence (AI) technologies interdisciplinary collaboration are poised growing complexity discovery. By fostering deeper understanding transformative this aims inspire innovative research directions further advance field chemistry.

Language: Английский

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Discovering Cell‐Targeting Ligands and Cell‐Surface Receptors by Selection of DNA‐Encoded Chemical Libraries against Cancer Cells without Predefined Targets

Angewandte Chemie, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Abstract Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live is an effective strategy for discovering cell‐targeting ligands. The DNA‐encoded library (DEL or DECL) technology has emerged as a robust tool drug discovery been successfully utilized identifying ligands biological targets. However, nearly all DEL selections predefined targets, while target‐agnostic interrogating the entire cell surface remain underexplored. Herein, we systematically optimized cell‐based selection method without A 104.96‐million‐member was selected MDA‐MB‐231 MCF‐7 breast cells, representing high low metastatic properties, respectively, which led identification of cell‐specific small molecules. We further demonstrated applications these photodynamic therapy targeted delivery. Finally, leveraging DNA tag compounds, identified α‐enolase (ENO1) receptor one targeting more aggressive cells. Overall, this work offers efficient approach molecule by using DELs demonstrates be useful identify receptors on

Language: Английский

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Discovering Cell‐Targeting Ligands and Cell‐Surface Receptors by Selection of DNA‐Encoded Chemical Libraries against Cancer Cells without Predefined Targets

Angewandte Chemie International Edition, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Abstract Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live is an effective strategy for discovering cell‐targeting ligands. The DNA‐encoded library (DEL or DECL) technology has emerged as a robust tool drug discovery been successfully utilized identifying ligands biological targets. However, nearly all DEL selections predefined targets, while target‐agnostic interrogating the entire cell surface remain underexplored. Herein, we systematically optimized cell‐based selection method without A 104.96‐million‐member was selected MDA‐MB‐231 MCF‐7 breast cells, representing high low metastatic properties, respectively, which led identification of cell‐specific small molecules. We further demonstrated applications these photodynamic therapy targeted delivery. Finally, leveraging DNA tag compounds, identified α‐enolase (ENO1) receptor one targeting more aggressive cells. Overall, this work offers efficient approach molecule by using DELs demonstrates be useful identify receptors on

Language: Английский

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Advances in DNA-empowered membrane surface engineering for artificial manipulation and visual analysis of cell-cell communication

TrAC Trends in Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 118280 - 118280

Published: April 1, 2025

Language: Английский

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Transduction of Lentiviral Vectors and ADORA3 in HEK293T Cells Modulated in Gene Expression and Alternative Splicing

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4431 - 4431

Published: May 7, 2025

For steady transgenic expression, lentiviral vector-mediated gene delivery is a commonly used technique. One question that needs to be explored how external vectors and overexpressed genes perturb cellular homeostasis, potentially altering transcriptional networks. In this study, two Human Embryonic Kidney 293T (HEK293T)-derived cell lines were established via transduction, one overexpressing green fluorescent protein (GFP) the other co-overexpressing GFP ADORA3 following puromycin selection ensure stable genomic integration. Genes with differentially transcript utilization (gDTUs) expressed (DEGs) across identified after short-read long-read RNA-seq. Only 31 discovered have changed in expression when was expressed, although hundreds of showed variations use. contrast, even co-overexpression alters more than 1000 genes, there are still less gDTUs. Moreover, DEGs linked overexpression play major role RNA splicing, whereas gDTUs highly number malignancies molecular mechanisms underlie them. analysis data from derived HEK293T, our findings provide important insights into changes alternative splicing.

Language: Английский

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Translation of Deoxyribonucleic Acid into Synthetic Alpha Helical Peptides for Darwinian Evolution

JACS Au, Journal Year: 2024, Volume and Issue: 4(10), P. 4013 - 4022

Published: Oct. 2, 2024

DNA-encoded libraries connect the phenotypes of synthetic molecules to a DNA barcode; however, most do not tap into potential Darwinian evolution. Herein, we report DNA-templated synthesis (DTS) architecture make peptides that are stabilized α-helical conformations via head-to-tail supramolecular cyclization. Using pilot library targeting MDM2, show repeated screening can amplify binder from lowest abundance in ranking correlates binding affinity. The study also highlights need design such chemistry avoids biases heterogeneous yield DTS.

Language: Английский

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